Engineering sustainable squalene analogues for novel vaccine adjuvant emulsions

设计用于新型疫苗佐剂乳液的可持续角鲨烯类似物

• 批准号: 10370340
• 负责人: Christopher B Fox
• 金额: $ 78.61万
• 依托单位: ACCESS TO ADVANCED HEALTH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-16 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370340
• 关键词: Adjuvant; Antigens; Biological; Biomedical Engineering; Brazil; California; Characteristics; Chemical Engineering; Chemicals; Data; Development; Dose; Emulsions; Engineering; Environmental Engineering technology; Evaluation; Event; Formulation; Government-Sponsored Programs; Human; Immune response; In Vitro; Industrialization; Infectious Diseases Research; Influenza; Influenza A Virus, H5N1 Subtype; Isoprene; Literature; Liver; Modification; Molecular Weight; North Carolina; Oils; Organism; Pathway interactions; Pharmacologic Substance; Plant Extracts; Plant Sources; Polymer Chemistry; Polymers; Preclinical Testing; Production; Program Sustainability; Property; Reagent; Recombinants; Reporting; Research Institute; Route; Shapes; Shark; Source; Squalene; Structure; Structure-Activity Relationship; Subunit Vaccines; Technology; Terpenes; Testing; Time; Triglycerides; Universities; Vaccine Adjuvant; Vaccine Production; Vaccines; Water; Work; Yeasts; analog; base; clinical development; experience; immunogenicity; improved; in vivo; in vivo Model; innovation; isoprenoid; monomer; mouse model; novel; novel vaccines; pandemic influenza; programs; research clinical testing; technology development; vaccine efficacy

Project Summary Global pandemic influenza vaccine production capacity is insufficient to meet the expected demand in the event of a highly lethal influenza pandemic. Current H5N1 vaccines require high antigen doses (e.g. 90 μg) or are combined with squalene-based oil-in-water emulsion adjuvants for enhanced and broadened immunogenicity as well as antigen dose sparing. Squalene is a naturally occurring oligoisoprene (i.e. a very low molecular weight polymer of isoprene) derived from shark liver, a source with sustainability concerns. Moreover, the biological mechanisms of action of squalene are still not well understood and no systematic comparison of the adjuvant activity of squalene emulsions compared to emulsions based on analog oligoisoprenes has been reported in the literature. This proposal defines a program to develop the sustainable production of various oligoisoprene analogues of squalene using bioengineered organisms and synthetic polymer chemistry. Selected structures will then be formulated in oil-in-water emulsions and evaluated for physicochemical stability. Importantly, we propose to identify structure-activity relationships (SAR) by employing squalene and oligoisoprene analogues in in vitro human and in vivo mouse models in combination with an H5N1 influenza antigen. Moreover, the ability to further enhance adjuvant activity by chemical modification to improve physicochemical properties of selected oligoisoprene structures will be evaluated. The technology generated could be applicable to many other vaccines that have need of emulsion-based adjuvants for antigen dose sparing or enhanced immune responses.

项目总结

项目成果

Formulated Phospholipids as Non-Canonical TLR4 Agonists.

• DOI: 10.3390/pharmaceutics14122557
• 发表时间: 2022-11-22
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Liang H;Lykins WR;Seydoux E;Guderian JA;Phan T;Fox CB;Orr MT
• 通讯作者: Orr MT

Screening of Oligomeric (Meth)acrylate Vaccine Adjuvants Synthesized via Catalytic Chain Transfer Polymerization.

• DOI: 10.3390/polym15183831
• 发表时间: 2023-09-20
• 期刊: Polymers
• 影响因子: 5
• 作者: Hege CS;Stimpson A;Sefton J;Summers J;Henke H;Dundas AA;Phan T;Kinsey R;Guderian JA;Sivananthan SJ;Mohamath R;Lykins WR;Ramer-Denisoff G;Lin S;Fox CB;Irvine DJ
• 通讯作者: Irvine DJ

Kilo-Scale GMP Synthesis of Renewable Semisynthetic Vaccine-Grade Squalene.

可再生半合成疫苗级角鲨烯的公斤级 GMP 合成。

• DOI: 10.1021/acs.oprd.3c00300
• 发表时间: 2023
• 期刊: Organic process research & development
• 影响因子: 3.4
• 作者: Fisher,KarlJ;Shirtcliff,Laura;Buchanan,Greg;Thompson,AndrewW;Woolard,FrankX;LaMunyon,DonaldH;Marshall,JonathanL;Baranouskas,MayaB;Voelker,RodgerB;Lusk,JasonS;Wells,CharlesE;Mohamath,Raodoh;Kinsey,Robert;Lykins,WilliamR
• 通讯作者: Lykins,WilliamR

Semi-synthetic terpenoids with differential adjuvant properties as sustainable replacements for shark squalene in vaccine emulsions.

• DOI: 10.1038/s41541-023-00608-y
• 发表时间: 2023-02-16
• 期刊: NPJ vaccines
• 影响因子: 9.2

Squalene Emulsion Manufacturing Process Scale-Up for Enhanced Global Pandemic Response.

扩大角鲨烯乳液生产工艺以增强全球流行病应对能力。

• DOI: 10.3390/ph13080168
• 发表时间: 2020
• 期刊: Pharmaceuticals (Basel, Switzerland)
• 作者: Phan,Tony;Devine,Christian;Laursen,ErikD;Simpson,Adrian;Kahn,Aaron;Khandhar,AmitP;Mesite,Steven;Besse,Brad;Mabery,KenJ;Flanagan,ElizabethI;Fox,ChristopherB
• 通讯作者: Fox,ChristopherB